Selinunte was founded on this coast in the seventh century BC and became one of the great Greek cities of Sicily; its temples still stand in the comune's territory, and the town's own founding myth ties it directly to that inheritance. The Roman name castrum veteranorum points to a settlement of veterans, and local tradition explains it as a refuge established inland for old Selinuntine soldiers escaping the unhealthy air of the coast.

The documented town begins under the Angevins. In 1299 Castelvetrano was granted to the Tagliavia . From the testament of Nino I Tagliavia in the mid-fourteenth century we know the place already had churches; the family itself lived between Palermo and Sciacca and only settled here with Baron Nino III . Wealth followed the land: Baron Bartolomeo's experiments with vine and wheat cultivation produced the surplus that paid for the enlargement of San Gandolfo in 1448 and for the rebuilding of the fifteenth-century churches.

Between the end of the fifteenth century and the beginning of the sixteenth, Castelvetrano became the capital of the Tagliavia-Aragona possessions and filled with art. Charles V raised it to a county in 1522 ; his son Philip II erected it into a principality in 1564 . The family name accumulated — Tagliavia, then Aragona, Cortes, Pignatelli — and they held the town until 1812 .

What they built is still the town's shape. The Palazzo Pignatelli , formerly the Castello di Bellumvider, covers more than ten thousand square metres over the remains of a thirteenth-century castle and was the princes' residence until the first half of the 1600s. San Domenico was begun in 1470 , raised by Giovanni Antonio and Giovan Vincenzo Tagliavia and decorated between 1574 and 1580 by Antonino Ferraro da Giuliana at the commission of Carlo d'Aragona. The Chiesa Madre of 1520 was decorated in the mid-seventeenth century by Antonino Ferraro the younger and Gaspare Serpotta. The church of San Giovanni , of the later sixteenth century, holds Antonello Gagini's statue of the Baptist of 1522 . The Carmine dates from 1509; the Purgatorio , built in 1653 at the will of Prince Diego Aragona Tagliavia and his daughter Giovanna, was placed for scenographic effect within the system of piazzas, which is exactly how it still works.

Outside the built-up area stands the Chiesa della Santissima Trinità di Delia , a fine piece of Arab-Norman architecture on a square plan with a central dome on four columns — older than the town's princely period and quite unlike everything else here.

The nineteenth century added the neoclassical Teatro Selinus by Giuseppe Patricolo, and the Museo Civico , which holds material from Selinunte including the Efebo — a rare bronze of about 480–460 BC, eighty-five centimetres high.